Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J19/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 by a lactone ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
  • C07J21/005—Ketals
  • C07J21/006—Ketals at position 3
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/18—Feminine contraceptives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
  • C07J1/0051—Estrane derivatives
  • C07J1/0081—Substituted in position 17 alfa and 17 beta
  • C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
  • C07J1/0092—Alkenyl derivatives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
  • C07J21/001—Lactones
  • C07J21/003—Lactones at position 17
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
  • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
  • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
  • C07J41/0016—Oximes
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
  • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton

Definitions

• the invention relates to steroids with a 17-spiromethylene lactone or lactol group, to their preparation, to a pharmaceutical composition comprising the same, and to their use for the manufacture of a contraceptive.
• Steroids with a 17-spiromethylene lactone group are known in the art, i.e. as disclosed in EP-A-558,416. Such steroids may have various hormonal activities, which can be assessed by their binding affinity to various receptors. Receptor binding studies have been performed for the 17-spiromethylene lactone steroids of EP-A-558,416 to demonstrate their hormonal activity. These steroids show remarkable antiglucocorticoid and antiprogestogenic activity, and may further have androgenic or anti-androgenic, glucocorticoid and progestogenic properties.
• steroids of EP-A-558,416 have a 5-membered 17-spiromethylene lactone group, the methylene group of which is juxtapositioned to the carbonyl group.
• glucocorticoid activity is considered to be an unwanted side-effect, and there is then a need for steroids which are selective progestogenic compounds with weak or non-existing glucocorticoid activity.
• Novel 17-spiromethylene lactone and lactol steroids have now been found possessing the desired receptor affinity, which is relatively higher for the progesterone receptor than for the glucocorticoid receptor.
• These novel steroids thus show selective progesterone receptor binding affinity.
• Their progesterone receptor binding affinity is much higher than that of known structurally related steroids.
• They are structurally different from the known 17-spiromethylene lactone steroids in that they have a 6- or 7-membered spirolactone or lactol group, whereas the methylene group is separated from the carbonyl (or hydroxymethylene) group by two or three methylene groups.
• these steroids show very weak glucocorticoid or antiglucocorticoid activity.
• the steroids of the present invention are very suitable for therapeutic use and side-effects resulting from (anti)glucocorticoid activity are believed to be substantially reduced.
• the steroids of the invention are steroids with a 17-spiromethylene lactone or lactol group, having formula I ##STR2## wherein R 1 is O, (H,H), (H,OR), or NOR, R being selected from H, (1-6C) alkyl and (1-6C) acyl; R 2 is H, (1-6C) alkyl optionally substituted by a halogen, (2-6C) alkenyl optionally substituted by a halogen, (2-6C) alkynyl optionally substituted by a halogen, or halogen; R 2 ' is H; or R 2 ' together with R 2 is a (1-6C) alkylidene group or (2-6C) alkenylidene group; or R 2 ' together with R 3 is a bond; R 3 is H, if not together with R 2 ' a bond; R 4 is (1-6C) alkyl; X is (CH 2 ) n or (C n H 2n-2 ) wherein n is 2 or
• 17-Spiromethylene lactone steroids of formula I wherein R 1 is O, R 4 is methyl, Y is O, and n is 2, are preferred.
• R 1 is O
• R 2 is (1-6C) alkyl or (2-6C) alkynyl
• R 2 ' and R 3 are H
• R 4 is methyl
• R 5 and R 6 are hydrogen
• X is (CH 2 ) 2
• Y is O
• the dotted line in the D-ring is not a bond and the other dotted line is a 4-5 bond.
• the most preferred 17-spiromethylene lactone steroids are (11 ⁇ ,17 ⁇ )-11-ethyl-17-hydroxy-3-oxo-19-norchola-4,20-dien-24-oic acid ⁇ -lactone and (11 ⁇ ,17 ⁇ )-17-hydroxy-3-oxo-11-(1-propynyl)-19-norchola-4,20-dien-24-oic acid ⁇ -lactone.
• (1-6C) alkyl means a branched or unbranched alkyl group having 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like.
• Preferred alkyl groups have 1-4 carbon atoms, and most preferred alkyl groups are ethyl and methyl.
• (2-6C) alkenyl means a branched or unbranched alkenyl group having at least one double bond and 2-6 carbon atoms.
• Preferred alkenyl groups have 2-4 carbon atoms, such as vinyl and propenyl.
• (2-6C) alkynyl means a branched or unbranched alkynyl group having at least one triple bond and 2-6 carbon atoms.
• Preferred alkynyl groups have 2-4 carbon atoms. Examples are ethynyl and 1-propynyl.
• (1-6C) alkylidene means a branched or unbranched alkylidene group having 1-6 carbon atoms.
• Preferred alkylidene groups have 1-4 carbon atoms, and most preferred is methylene.
• (2-6C) alkenylidene means a branched or unbranched alkenylidene group having 2-6 carbon atoms.
• Preferred alkenylidene groups have 2-4 carbon atoms, such as ethenylidene.
• (1-6C) acyl means an acyl group derived from an aliphatic carboxylic acid having 1-6 carbon atoms. Acetyl is the most preferred acyl group.
• halogen means fluorine, chlorine, bromine or iodine. Chlorine is the preferred halogen.
• the progestogenic steroids of this invention can be used as contraceptives in mammals, more particularly in humans and animals.
• the compounds of the invention further exhibit the usual activities known for progestogens. For example, they can be used to treat menstrual disorders and hormone-dependent tumors and they can also be applied in hormone replacement therapy.
• the steroids of formula I may be prepared according to well-known methods described and used for the preparation of analogous steroids.
• a suitable process for the preparation of some of the steroids of the invention is characterized in that a compound having formula II ##STR3## wherein
• R 1 ' is O,(H,H) or (H,OR), R being selected from H, (1-6C) alkyl and (1-6C) acyl, or a protected derivative thereof;
• R 2 is H, (1-6C) alkyl optionally substituted by a halogen, (2-6C) alkenyl optionally substituted by a halogen, (2-6C) alkynyl optionally substituted by a halogen, or halogen;
• R 2 ' is H; or R 2 ' together with R 2 is a (1-6C) alkylidene group or a (2-6C) alkenylidene group; or R 2 ' together with R 3 is a bond;
• R 3 is H if not together with R 2 ' a bond;
• R 4 is (1-6C) alkyl; one of R 5 and R 6 is hydrogen and the other is hydrogen or (1-6C) alkyl; each Q is independently selected from H, (1-6C) alkyl and (7-9C) pheny
• 17-keto steroids can be prepared from the corresponding 17-keto steroids.
• These 17-keto steroids can be obtained according to the process as disclosed in DE 2,805,490, or as described in Van den Broek et al., Steroids Vol. 30, 481-510 (1977).
• said 17-keto steroids are condensed with a 2-metallated-5-(protected hydroxy)-1-pentene or with a 2-metallated-6-(protected hydroxy)-1-hexene, for example with 2-lithio-5-trimethylsilyloxy-1-pentene or with 2-lithio-6-trimethylsilyloxy-1-hexene, followed by removal of the protective group(s), the compounds of formula II are obtained.
• Suitable protective groups are known in the art, for example from T. W. Green: Protective Groups in Organic Synthesis (Wiley, NY, 1981).
• the addition can also be performed with a suitably protected carboxylic acid derivative, e.g. an ortho ester, or with a suitably protected aldehyde, e.g. 4,5-dihydro-2-(3'-lithiobut-3'-en-1'-yl)-1,3-dioxolane.
• a metal salt of the alcohol can be used, i.e. no protecting group is present.
• metals or techniques known in metallo-organic chemistry e.g. lithium, zinc, magnesium, cerium
• aromatic radical-anion compounds such as lithium naphthalenide.
• the activating group on the alkene moiety can be a halogen, like bromine or iodine, or a substituted metal, such as a trialkyltin or trialkylgermanium group.
• the intermediates thus obtained can also be prepared by treatment of suitably protected derivatives of 17,24-dihydroxy-21-norcholan-20-ones with reagents capable of converting a carbonyl group to an alkylidene group, such as Wittig, Horner, Peterson or similar reagents known in the art.
• cyclic acetals are particularly useful, e.g. 1,2-ethanediyl acetal, 2,2-dimethylpropane-1,3-diyl acetal, or acyclic acetals or thioacetals. Similar groups known in the art, e.g. enol ethers, can also be employed.
• oxidizing agents known in the art, such as chromium(VI)oxide and silver carbonate on celite.
• the order in which the reactions are performed can be changed, e.g. oxidation of a 17,24-diol to a lactone can be performed prior to the deprotection of the carbonyl group at C-3.
• Lactols (Y is H,OH) can be prepared by partial oxidation of a compound of formula II by methods known in the art, for instance by a Swern oxidation.
• protected OH means a hydroxy group which is protected in a manner as usual for the protection of hydroxy groups, for example as disclosed in T. W. Green.
• the steroids of the invention can be prepared from compounds of formula III ##STR4## wherein R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , n, Q, and the dotted lines have the meanings as given for the compounds of formula II, and L is a leaving group, is converted by base-catalyzed ring-closure into a steroid with a 17-spiromethylene lactone group, optionally followed by alkylation, phenylalkylation, acylation, halogenation optionally followed by dehydrohalogenation, and/or reduced into a compound wherein Y is (H,OH), after which the optionally present protective group is removed, optionally followed by conversion of a compound with formula I wherein R 1 is O into the corresponding compound wherein R 1 is NOR, as previously defined.
• the base-catalyzed ring closure can be performed by sodium or potassium bis(trimethylsilyl)amide or other hindered bases, preferably in an ether, for instance tetrahydrofuran and the like.
• 17-keto steroids can be obtained according to the process as disclosed in DE 2,805,490, or as described in Van den Broek et al., Steroids Vol. 30, 481-510 (1977).
• 17-keto steroids When said 17-keto steroids are condensed with a 2-metallated-3,3-dialkoxy-1-propene or a 2-metallated-4,4-dialkoxy-1-butene, for instance with 2-lithio-3,3-diethoxy-1-propene or 2-lithio-4,4-diethoxy-1-butene, followed by selective hydrolysis of the dialkyl acetal function and reduction of the resulting aldehyde, 17-hydroxy-20-(hydroxymethyl)pregn-20-ene or 17,23-dihydroxy-19,24-dinorchol-20-ene derivatives can be prepared.
• the 17-hydroxy group is esterified into a suitable ester, for instance an acetate.
• the other hydroxy group is converted to a leaving group, for example by reaction with tosyl chloride to give a tosylate.
• Suitable leaving groups are known in the art, for example from A. L. Ternay: Contemporary Organic Chemistry (2nd ed., W. B. Saunders Company, 1979, see pages 158 and 170-172).
• Preferred leaving groups are halogens such as chlorine, bromine, and iodine, and in particular the tosyloxy group.
• Alkylation and phenylalkylation can be performed by methods known in the art, for instance by using lithium diisopropylamide (LDA) or potassium bis(trimethylsilyl)-amide and the like.
• LDA lithium diisopropylamide
• potassium bis(trimethylsilyl)-amide potassium bis(trimethylsilyl)-amide
• 2-metallated dialkoxyalkenes from alkenylhalogenides
• metals or techniques known in metallo-organic chemistry such as alkyllithium and the ones described above, can be used.
• the activating group on the alkene moiety can be an halogen, like bromine or iodine, or a substituted metal, such as a trialkyltin or trialkylgermanium group.
• the synthesis of 17-hydroxy-20-(hydroxymethyl)pregn-20-enes can also be achieved by addition of suitably protected 2-metallo-2-propen-1-ols to estran-17-ones, followed by deprotection of the hydroxy group.
• the conversion of 17-hydroxy-20-(hydroxymethyl)pregn-20-enes to the corresponding 17-mono-acetates or 17-mono-propionates can be accomplished using acidic catalysts, e.g. phosphorus oxychloride or oxalic acid in trialkyl orthoacetate or trialkyl orthopropionate.
• Some of the lactones of this invention can also be prepared by selective reduction of 17-hydroxychola-20,22-dien-24-oic acid ⁇ lactones.
• lactones of the invention can also be prepared by lactonisation of a 17-hydroxycholan-24-oic acid, or by lactonisation of an ester of such an acid (e.g.
• an acetate, a t-butyl, or a trialkylsilyl ester can also be prepared from a 17-hydroxy-24-norchola-23,23-dicarboxylic acid, or from mono- or di-esters of such an acid, or from 17-hydroxycholano-24-nitriles or a 23-cyano-17-hydroxycholan-24-oic acid or esters thereof.
• the ⁇ lactones can also be prepared by a similar procedure from a 17-hydroxycholane-24-carboxylic acid or from an ester of such an acid, or they can be prepared from a 17-hydroxycholane-24,24-dicarboxylic acid or from mono- or di-esters of such an acid, or be prepared from 17-hydroxycholane-24-carbonitriles or from 24-cyano-17-hydroxycholane-24-carboxylic acids or esters thereof.
• the compounds of the invention may be administered enterally or parenterally, and for humans preferably in a daily dosage of 0,0001-10 mg per kg body weight.
• the compounds may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories.
• the compounds can also be applied as an injection preparation in the form of a solution, suspension, emulsion, or as a spray, e.g. a nasal spray.
• dosage units e.g.
• Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts.
• Example 2 (17 ⁇ )-17-Hydroxy-11-methylene-3-oxo-19-norchola-4,20-dien-24-oic acid ⁇ lactone (Example 2) was also prepared from (17 ⁇ )-17,24-dihydroxy-11-methylene-19-norchola-4,20-dien-3-one via a stepwise oxidation process as follows:
• step i 2.73 g of the product of the previous step were converted to 2.22 g of a 6:4 mixture of (3 ⁇ ,17 ⁇ )-3-methoxy-11,20-dimethylene-19-norpregn-4-ene-17,21-diol and (3 ⁇ ,17 ⁇ )-3-methoxy-11,20-dimethylene-19-norpregn-4-ene-17,21-diol, which were used as such in the following step.
• step iii of Example 4 2.22 g of the product of the previous step were acetylated at the 17-hydroxy group giving 1.04 g of (3 ⁇ ,17 ⁇ )-3-methoxy-11,20-dimethylene-19-norpregn-4-ene-17,21-diol 17-acetate and 0.75 g of (3 ⁇ ,17 ⁇ )-3-methoxy-11,20-dimethylene-19-norpregn-4-ene-17,21-diol 17-acetate.
• step i of Example 1 29.7 g of the latter steroid were converted to 42.07 g of a mixture of starting material and (17 ⁇ )-17-hydroxy-24-trimethylsilyloxy-19-norchola-5(10),9(11),20-trien-3-one cyclic 1,2-ethanediyl acetal, which were used as such in the following step.
• step i of Example 13 10.05 g of the lactone mentioned above were converted to 4.17 g of (17 ⁇ )-23,23-dibromo-3,3- 1,2-ethanediylbis(oxy)!-17-hydroxy-19-norchola-5,20-dien-24-oic acid ⁇ lactone.
• step i of Example 1 30.0 g of the latter steroid were converted to 45.1 g of a mixture of starting material and (7 ⁇ ,17 ⁇ )-17-hydroxy-7-methyl-24-trimethylsilyloxy-19-norchola-5(10),20-dien-3-one dimethyl acetal, which were used as such in the following step.
• the progesterone affinity of the compounds of the invention was measured for cytoplasmic progesterone receptors present in human breast tumor cells (MCF-7 cells, incubation time 16 h, temperature 4° C.) and compared with the affinity of (16 ⁇ )-16-ethyl-21-hydroxy-19-norpregn-4-ene-3,20-dione (according to the procedure described by E. W. Bergink et al., J. Steroid Biochem., Vol. 19, 1563-1570 (1983)).
• the glucocorticoid affinity of the compounds of the invention was measured for glucocorticoid receptors present in intact human multiple myeloma cells (IM-9 cells, incubation time 1 h, temperature 37° C.) and compared with the affinity of dexamethasone (according to the procedure described by H. J. Kloosterboer et al., J. Steroid Biochem., Vol. 31, 567-571 (1988)).
• the compounds of the invention have a much higher PR/GR ratio than the prior art compounds, which ratio's are usually >1 in contrast to the prior art compounds, which PR/GR ratio's are ⁇ 1.
• This means that the prior art compounds show relatively higher receptor binding affinity to the glucocorticoid receptor than to the progesterone receptor, whereas the compounds of the invention have a relatively favourable affinity to the progesterone receptor and relatively low affinity to the unfavourable glucocorticoid receptor.
• Compounds having relatively low affinity to the progesterone receptor may be suitable pro-drugs.

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